Патент USA US2265185код для вставки
Patented Dec. 9, 1941 ‘2,265,185 UNITED STATES PATENT OFFICE 2,265,185 BASIC ESTERS AND AMIDES AND PROCESS OF PRODUCING SAME Karl Miescher, Riehen, and Karl Hoffmann, Ba- _ ‘ sel, Switzerland, assignors, by mesne assign ments, to Ciba Pharmaceutical Products, In corporated, Summit, N. J., a corporation of New Jersey ' No Drawing. Application July 1, 1939, Serial No. ' 283,319. In Switzerland August 5, 1938 8 Claims. (Cl. 260—468) concentrated sulfuric acid, 2 parts of activated This invention relates to the manufacture of platinum are added and the whole is shaken with hydrogen at about 60° C. When reduction is ?n ished the liquid is decanted from the platinum basic esters and amides of alicyclic or aryl-ali cyclic fatty acids by treating with a reducing agent a basic ester or amide of a fatty acid con ' and the solvent is evaporated. taining‘one or more unsaturated nuclei. The saturation of. the unsaturated nuclear double-linkages in accordance with the invention may be brought about by methods in themselves known. In this connection'reference may be The oil which re mains is shaken with water, potassium carbonate solution and ether and the ethereal solution is washed with water, dried by means of potassium carbonate and the ether is evaporated. In this manner thereis obtained an oil of boiling point made to Houben-Weyl, “Die Methoden der Organischen Chemie," 3rd edition, vol. 2, (1925), 154—157° C. under 0.2 mm. pressure. This oil is dissolved in petroleum-ether and gaseous hydro gen chloride is passed over the solution, whereby the hydrochloride is precipitated: it may be re crystallized from a, mixture of alcohol and petro leum-ether. There is thus obtained in prepon pages 326 et seq. Reduction by a catalytic meth od, for instance with use of noble metals such as platinum as catalysts, is particularly advan tageous. There may be used as parent materials, any basic esters and amides of fatty acids which con derating quantity ‘dicyclohexyl acetic acid di tain unsaturated nuclei. There may here be mentioned by way of example basic esters and ethylamino ethanol ester hydrochloride of melt ing point 165-“166° C., which is more sparingly amides of phenyl-fatty acids, naphthalene-fatty soluble in petroleum-ether, and a smaller quan acids and the like. These parent materials may be prepared according to known processes, for ex ample‘ as described in Patents 2,079,962 and tity of phenyl-cyclohexyl acetic acid diethyl amino ethanol ester hydrochloride of melting point 145—147° C., which is more readily soluble in 2,009,144. petroleum-ether. ‘ matic carboxylic acids, for example atropine, scopolamine, diphenyl acetic acid diethylamino catalysts. , The dicyclohexyl ethanol ester and others undergo a hydrolytic de composition when their salts are kept in aqueous solution. Surprisingly it has been found that the . . acetic acid-diethylamino ethanol ester forms a sulfocyanide of melting point 93-95° C., a nitrate of melting point 102-104° C., a tartrate of melting point 63° C. with decomposition, a phosphate of melting point 112-114° C., a citrate of melting point 155-158° C. new basic esters have a very considerably greater stability. Thus for example the sulfate of di cyclohexyl acetic acid diethylamino ethanol ester and the hydrochloride of phenyl-cyclohexyl acetic acid diethylamino ethanol ester can be sterilized for 10 hours without undergoing decomposition, whereas aqueous solutions of atropine sulfate and of di-phenyl acetic acid diethylamino ethanol ester hydrochloride decompose already on stand ing for a long time at ordinary temperature and . There may also be used other catalysts, such as for instance a palladium catalyst or mixture of The hitherto known basic esters of fatty-aro 25 and an oxalate of melting point 120-124° C. ' 32 parts of dicyclohexyl acetic acid diethyl amino ethanol'ester and 60 parts of allylbromide are heated in 500 parts of ethyl acetate for 3 . hours to boiling, the whole is then cooled and 40 considerably more rapidly when the solution is boiled. It is furthermore quite surprising that ?ltered. The bromallylate so obtained, having a melting point 152-153° C., can be recrystallized from a mixture of ethyl-acetate and acetone. In a similar manner the following quaternary salts of dicyclohexyl acetic acid-diethylamino ethanol ester can also be prepared: bromomethylate. * melting point 176-177.5°-C.: bromethylate, melt_ ing point 178-180° 0.; and bromobenzylate melt spasmolytic activity, since all hitherto known ing point 155-156° C. spasmolytically active basic esters belong to the fatty-aromatic series. ' Example 2 The following examples illustrate the invention, also the new esters are very active pharmacologi cal substances. It could in no way be foreseen , that the products of the invention would exhibit 1.5 parts of di-phenyl acetic acId-Z-diethyl the parts being by weight: Example 1 31 parts of di-phenyl acetic acid-2-diethyl amino-ethyl-amide are dissolved in 20 ‘parts of glacial acetic acid and a small quantity of con; amino ethanol ester, are dissolved in a mixture of 200 parts of glacial acetic acid and 8 parts of :15 centrated sulfuric acid is added. 0.1 part of activated platinum is then added to the solution and the whole is shaken with hydrogen at about 2 2,265,185 50° C. When the calculated quantity of hydro tropic acid with hydrogen in the presence of gen has been absorbed the whole is allowed to platinum), the tau-dicyclohexyl-e-hydroxy-acetic cool, the liquid is decanted from the platinum and acid diethylamino ethanol ester hydrochloride of melting point 189-191” C. (a,a-dicyclohexyl-u hydroxy-acetic acid of melting point 143-144" C. can be prepared for example by catalytic reduc tion of benzilic acid), the a-phenyl-a-cyclohexyl a-hydroxy-acetic acid diethylamino ethanol ester, the a-cycloheXyl-hydracrylic acid scopine ester the solvent is evaporated. To the oil which re mains water and a sodium carbonate solution are vadded, dicyclohexyl-acetic acid-Z-diethylamino ethyl-amide being thereby precipitated as a solid substance. It is ?ltered with suction and washed with water. The new product may be recrystal lized for example from alcohol of 50 per cent 10 hydrochloride of melting point 209-212“ C., the a strength and has the melting point 122° C. By conducting the reduction under somewhat milder conditions there is obtained phenylcyclo hexyl acetic acid diethylamino ethyl amide of melting point 84-86“ C. which forms a hydro 15 chloride of melting point l69-l71.5° C. ' cyclohexyl~a-propyl acetic acid diethylamino ethanol ester hydrochloride of melting point 106 108° C. (a-cyclohexyl-a-propyl-acetic acid can be prepared for example by a catalytic reduction of e-phenyl-a-propyl-acetic acid with hydrogen in glacial acetic acid solution in the presence of platinum), the cyclohexyl-acetic acid diethyl amino ethanol ester hydrochloride of melting 31 parts of di-phenyl acetic acid-2-diethyl point 116-118° C., the phenyl-cyclohexyl acetic amino-ethanol ester hydrochloride are dissolved 20 acid ester of ecgoninemethyl ester, the phenyl in 300 parts of glacial acetic acid, 3 parts of an dimethylaminocyclohexyl-acetic acid diethyl activated platinum catalyst are added and the amino ethanol ester and the cyclohexyl-diethyl whole is shaken with hydrogen at room tempera amino ethyl acetic acid diethylamino ethanol Example '3 ture. The reaction mixture is worked up in the ester. manner indicated in Example 1, whereby there 25 What we claim is: > are obtained the compounds already described in 1. A process for the manufacture of basic esters that example. and amides, which comprises treating with a 10 parts of phenyl-cyclohexyl acetic acid di reducing agent a member of the group consist ethylamino ethanol ester and 6 parts of methyl ing of the basic esters and amides of aryl sub bromide are allowed to stand in 40 parts of ethyl 80 stituted lower fatty acids. ester at ?rst in the cold for several hours and 2. A process for the manufacture of basic esters then at room temperature. After some time the and amides, which comprises treating with a re bromomethylate of melting point 174-179" C. ducing agent a member of the group consisting crystallized in the form of beautiful crystals. of the basic esters and amides of poly phenyl sub In a similar manner there may be obtained 35 stituted lower, fatty acids. for example the piperidino-ethanol ester, the di 3. A process for the manufacture of basic esters ethylamino-butanol ester, the morpholino ethanol which comprises treating with a reducing agent ‘ester, the ethyl-acetoxyethyl-amino ethanol ester, basic esters of di-phenyl acetic acid. . the ethyloxypropyl-amino-ethanol ester, the 4. A process for the manufacture of basic esters methyl-propyl-amino ethanol ester and the di which comprises treating with a reducing agent methylaminocyclohexanol ester of the phenyl di-phenyl acetic acid diethylamino ethanol ester. cyclohexyl acetic acid, as well as quaternary salts 5. The nuclear reduction products of amino of these compounds. alkyl esters and amides of aryl substituted lower In quite an analogous manner there can also fatty acids. be obtained for example the diethylamino ethanol 6. The nuclear reduction products of amino esters of phenylcyclohexyl-propionic acid and alkyl esters and amides of poly phenol substituted phenylcyclohexylbutyric acid, basic esters of di lower fatty acids. cyclopentyl acetic acid, the dicyclohexyl acetic 7. The nuclear reduction products of amino acid tropine ester, which forms a hydrochloride alkyl esters of 'di-phenyl acetic acid. of melting point 260-261" C., the u-cyclohexyl hydracrylic acid-tropine ester sulfate of melting point 211-213° C.‘ (a-cyclohexylhydracrylic acid can be prepared’ for example by reduction of 8. The nuclear reduction products of di-phenyl acetic acid diethylamino ethanol ester. KARL MIESCHER. KARL HOFFMANN.